Histamine H2 receptor stimulation upregulates TH2 chemokine CCL17 production in human M2a macrophages Susanne Mommert, PhD, Karl Gregor, MD, Kristine.

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Presentation transcript:

Histamine H2 receptor stimulation upregulates TH2 chemokine CCL17 production in human M2a macrophages Susanne Mommert, PhD, Karl Gregor, MD, Kristine Rossbach, DVM, Katrin Schaper, DVM, Torsten Witte, MD, Ralf Gutzmer, MD, Thomas Werfel, MD Journal of Allergy and Clinical Immunology Volume 141, Issue 2, Pages 782-785.e5 (February 2018) DOI: 10.1016/j.jaci.2017.06.023 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Stimulation via H2R significantly upregulates CCL17 mRNA expression and protein production in IL-4–activated human M2a macrophages. A and B, IL-4 (20 ng/mL)-activated M2a macrophages were stimulated with histamine, 2-pyridylethylamine (H1R agonist), amthamine (H2R agonist), 4-MH (H2R/H4R agonist), and ST-1006 (H4R agonist) for 24 hours. C, E, and F, The upregulation of CCL17 mRNA expression in response to histamine, amthamine, and 4-MH was significantly blocked by preincubation with the selective H2R antagonist ranitidine 30 minutes before stimulation with receptor agonists. D and G, The selective H4R antagonist JNJ7777120 had no effect. The concentration of 10 μM was used for all ligands. CCL17 mRNA expression was detected by quantitative PCR. CCL17 protein concentrations were analyzed by ELISA. The mRNA- and protein expression were normalized to the IL-4–stimulated samples (IL-4–stimulated M2a macrophages produced in median 470 pg/mL CCL17, ranging from 97 pg/mL to 770 pg/mL). 2-Pyrid, 2-pyridylethylamine; Amth, amthamine; Hist, histamine; JNJ, JNJ7777120; NS, nonstimulated; Ran, ranitidine. Significant differences, as determined by the Wilcoxon signed rank test, are indicated as follows: *P < .05; **P < .01; ***P < .001; medians are shown in the graphs. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Stimulation via H2R significantly upregulates CCL17 mRNA expression and protein production in IL-13–activated human M2a macrophages. IL-13 (15 ng/mL)-activated M2a macrophages were stimulated with histamine, 2-pyridylethylamine (H1R agonist), amthamine (H2R agonist), 4-MH (H2R/H4R agonist), and ST-1006 (H4R agonist). The upregulation of CCL17 mRNA expression and protein production in response to histamine, amthamine, and 4-MH was significantly blocked by preincubation with the selective H2R antagonist ranitidine. The concentration of 10 μM was used for all ligands. A-C, CCL17 mRNA expression was detected by quantitative PCR. D-F, CCL17 protein concentrations were analyzed by ELISA. The mRNA- and protein expression were normalized to the IL-13–stimulated samples (IL-13–stimulated M2a macrophages produced in median 216 pg/mL CCL17, ranging from 5.5 pg/mL to 549 pg/mL). G and H, Stimulation of the H1R or H4R shows no effect. 2-Pyrid, 2-pyridylethylamine; Amth, amthamine; Hist, histamine; JNJ, JNJ7777120; NS, nonstimulated; Ran, ranitidine. Significant differences, as determined by the Wilcoxon signed rank test, are indicated as follows: *P < .05; **P < .01; medians are shown in the graphs. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 The spontaneous secretion of CCL17 and the IL-4–induced CCL17 production in M2 macrophages are almost similar in cells obtained from healthy donors compared with cells obtained from patients with AD. The IL-13–induced CCL17 secretion is attenuated in M2 macrophages obtained from patients with AD as compared with healthy controls. Stimulation via H2R upregulates CCL17 protein production in IL-4– and IL-13–activated human M2a macrophages obtained from patients with AD. A and C, Fully differentiated M2 macrophages obtained from healthy controls or patients with AD were stimulated with IL-4 (20 ng/mL) or IL-13 (15 ng/mL) for 48 hours or left unstimulated. CCL17 protein production was analyzed by ELISA. B and D, IL-4– or IL-13– activated M2a macrophages obtained from patients with AD were stimulated with histamine, amthamine (H2R agonist), and 4-MH (H2R/H4R agonist) for 24 hours. The concentration of 10 μM was used for all ligands. CCL17 protein concentrations were analyzed by ELISA. The protein expression was normalized to the IL-4– or IL-13–stimulated samples (IL-4– or IL-13–stimulated M2a macrophages obtained from patients with AD produced in median 372 pg/mL or 38.6 pg/mL CCL17, ranging from 7.5 pg/mL to 2194 pg/mL or 10.4 pg/mL to 612.2 pg/mL, respectively). AD, Atopic dermatitis; Amth, amthamine; Hist, histamine; NS, nonstimulated. Significant differences, as determined by the Wilcoxon signed rank test, are indicated as follows: *P < .05; **P < .01; ***P < .001; medians are shown in the graphs. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Stimulation with histamine or with selective histamine receptor agonists has no effect on protein production of CCL22 in IL-4– or IL-13–activated human M2a macrophages. Fully differentiated M2 macrophages were activated with IL-4 (20 ng/mL) or IL-13 (15 ng/mL) for 24 hours. M2a macrophages were stimulated with histamine, amthamine (H2R agonist), 4-MH (H2R/H4R agonist), and ST-1006 (H4R agonist) for 24 hours. The concentration of 10 μM was used for all agonists. A, CCL22 protein concentrations in IL-4– activated M2a macrophages. B, CCL22 protein concentrations in IL-13–activated M2a macrophages. Protein concentrations were analyzed by ELISA. The protein expression was normalized to the IL-4– or IL-13–stimulated samples (IL-4–stimulated M2a macrophages produced in median 167117 pg/mL CCL22, ranging from 89,268 pg/mL to 294,926 pg/mL). (IL-13–stimulated M2a macrophages produced in median 115,200 pg/mL CCL22, ranging from 16,960 pg/mL to 1,312,000 pg/mL). ∗P < .05; medians are indicated in the graphs. Amth, Amthamine; Hist, histamine; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Stimulation via H2R significantly upregulates CCL17 mRNA expression and protein production in IL-4–activated human M2a macrophages in a time- and dose-dependent manner. The highest expression of CCL17 was found when the cells were stimulated for 24 hours with a concentration of 10 μM of the HR ligands. A and B, M2a macrophages were stimulated for different time periods with histamine, amthamine, and 4-MH as indicated. C, M2a macrophages were stimulated with different concentrations of histamine, amthamine, and 4-MH as indicated for 24 hours. A and C, CCL17 mRNA expression was detected by quantitative PCR. B, CCL17 protein concentrations were analyzed by ELISA. The mRNA- and protein expression were normalized to the IL-4–stimulated samples (IL-4–stimulated M2a macrophages produced in median 470 pg/mL CCL17, ranging from 97 pg/mL to 770 pg/mL). Amth, Amthamine; Hist, histamine; NS, nonstimulated. Significant differences, as determined by the Wilcoxon signed rank test, are indicated as follows: *P < .05; **P < .01; medians are shown in the graphs. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Stimulation via H2R significantly upregulates CCL17 but not CCL22 protein production in IL-4– or IL-13–activated human monocytes. IL-4 (20 ng/mL)- or IL-13 (15 ng/mL)-activated monocytes were stimulated with histamine, amthamine (H2R agonist), 4-MH (H2R/H4R agonist), and ST-1006 (H4R agonist) for 24 hours. The protein expression was normalized to the IL-4 or IL-13 stimulated samples. A and B, CCL17 production was assessed by ELISA (IL-4– or IL-13–stimulated M2a macrophages produced in median 303 pg/mL or 120 pg/mL CCL17, ranging from 147 pg/mL to 655 pg/mL or from 34 pg/mL to 771 pg/mL). C and D, CCL22 production was assessed by ELISA (IL-4– or IL-13–stimulated M2a macrophages produced in median 29,790 pg/mL or 23,310 pg/mL CCL22, ranging from 6,576 pg/mL to 116,900 pg/mL or from 5,237 pg/mL to 104,700 pg/mL). The concentration of 10 μM was used for all ligands. Amth, Amthamine; Hist, histamine; NS, nonstimulated. Significant differences, as determined by the Wilcoxon signed rank test, are indicated as follows: *P < .05; medians are shown in the graphs. Journal of Allergy and Clinical Immunology 2018 141, 782-785.e5DOI: (10.1016/j.jaci.2017.06.023) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions